Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Allosteric modulator Desformylflustrabromine relieves the inhibition of α2β2 and α4β2 nicotinic acetylcholine receptors by β-amyloid(1-42) peptide.
Pandya A, Yakel JL.
???displayArticle.abstract???
Nicotinic acetylcholine receptors (nAChRs) are pentameric transmembrane proteins that belong to the cys-loop ligand-gated ion channel family. These receptors are widely expressed in the brain and implicated in the pathophysiology of many neurological conditions, including Alzheimer's disease (AD), where typical symptoms include the loss of cognitive function and dementia. The presence of extracellular neuritic plaques composed of β amyloid (Aβ(1-42)) peptide is a characteristic feature of AD. Desformylflustrabromine (dFBr) is a positive allosteric modulator (PAM) for α4β2 nAChRs since it increases peak ACh responses without inducing a response on its own. Previously, the effect of dFBr on the α2β2 nAChR subtype was not known. The action of dFBr was tested on α2β2 receptors expressed in Xenopus oocytes. It was found that dFBr is also a PAM for the α2β2 receptor. Next we tested whether dFBr had any effect on the previously known block of both the α4β2 and α2β2 receptors by Aβ(1-42). We found that the functional blockade of ACh-induced currents in oocytes expressing α4β2 and α2β2 receptors by Aβ(1-42) was prevented by dFBr. We conclude that dFBr is a positive allosteric modulator for both α4β2 and α2β2 subtypes of nAChRs and that it also relieves the blockade of these receptors by Aβ(1-42). This study demonstrates that PAMs for the non-α7 nAChRs have the potential to develop into clinically applicable drugs for AD and other disorders.
Court,
Nicotinic receptor abnormalities in Alzheimer's disease.
2001, Pubmed
Court,
Nicotinic receptor abnormalities in Alzheimer's disease.
2001,
Pubmed Coyle,
Alzheimer's disease: a disorder of cortical cholinergic innervation.
1983,
Pubmed Dineley,
beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes.
2002,
Pubmed
,
Xenbase Dougherty,
Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex.
2003,
Pubmed Flores,
A subtype of nicotinic cholinergic receptor in rat brain is composed of alpha 4 and beta 2 subunits and is up-regulated by chronic nicotine treatment.
1992,
Pubmed Fu,
Beta-amyloid peptide activates non-alpha7 nicotinic acetylcholine receptors in rat basal forebrain neurons.
2003,
Pubmed Gay,
Gating of nicotinic ACh receptors; new insights into structural transitions triggered by agonist binding that induce channel opening.
2007,
Pubmed Gopalakrishnan,
Stable expression, pharmacologic properties and regulation of the human neuronal nicotinic acetylcholine alpha 4 beta 2 receptor.
1996,
Pubmed Grassi,
Amyloid beta(1-42) peptide alters the gating of human and mouse alpha-bungarotoxin-sensitive nicotinic receptors.
2003,
Pubmed
,
Xenbase Huang,
Apolipoprotein E fragments present in Alzheimer's disease brains induce neurofibrillary tangle-like intracellular inclusions in neurons.
2001,
Pubmed Jones,
Nicotinic receptors in the brain: correlating physiology with function.
1999,
Pubmed Kim,
Synthesis of desformylflustrabromine and its evaluation as an alpha4beta2 and alpha7 nACh receptor modulator.
2007,
Pubmed
,
Xenbase Lamb,
Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by beta-amyloid1-42 peptide.
2005,
Pubmed
,
Xenbase Levin,
Nicotinic acetylcholine involvement in cognitive function in animals.
1998,
Pubmed Lindstrom,
Structure and function of neuronal nicotinic acetylcholine receptors.
1996,
Pubmed Lindstrom,
Neuronal nicotinic acetylcholine receptors.
1996,
Pubmed Liu,
A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides.
2009,
Pubmed
,
Xenbase Liu,
beta -Amyloid peptide blocks the response of alpha 7-containing nicotinic receptors on hippocampal neurons.
2001,
Pubmed Lysek,
Isolation and structure elucidation of deformylflustrabromine from the North Sea bryozoan Flustra foliacea.
2002,
Pubmed McQuiston,
Nicotinic receptor activation excites distinct subtypes of interneurons in the rat hippocampus.
1999,
Pubmed Nathan,
Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro.
1994,
Pubmed Paterson,
Neuronal nicotinic receptors in the human brain.
2000,
Pubmed
,
Xenbase Perry,
Cholinergic receptors in cognitive disorders.
1986,
Pubmed Peters,
Prenylated indole alkaloids from Flustra foliacea with subtype specific binding on NAChRs.
2004,
Pubmed Pettit,
beta-Amyloid(1-42) peptide directly modulates nicotinic receptors in the rat hippocampal slice.
2001,
Pubmed Picciotto,
Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain.
1995,
Pubmed Sala,
Potentiation of human alpha4beta2 neuronal nicotinic receptors by a Flustra foliacea metabolite.
2005,
Pubmed
,
Xenbase Schmechel,
Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease.
1993,
Pubmed Sudweeks,
Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons.
2000,
Pubmed Weltzin,
Pharmacological characterization of the allosteric modulator desformylflustrabromine and its interaction with alpha4beta2 neuronal nicotinic acetylcholine receptor orthosteric ligands.
2010,
Pubmed
,
Xenbase Whiting,
Functional acetylcholine receptor in PC12 cells reacts with a monoclonal antibody to brain nicotinic receptors.
,
Pubmed Wu,
beta-Amyloid directly inhibits human alpha4beta2-nicotinic acetylcholine receptors heterologously expressed in human SH-EP1 cells.
2004,
Pubmed Yakel,
Functional and molecular characterization of neuronal nicotinic ACh receptors in rat hippocampal interneurons.
2004,
Pubmed Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase
